Zinc finger protein Zfp335 controls early T-cell development and survival through ß-selection-dependent and -independent mechanisms.
Elife
; 112022 02 03.
Article
em En
| MEDLINE
| ID: mdl-35113015
ABSTRACT
T-cell development in the thymus undergoes the process of differentiation, selective proliferation, and survival from CD4-CD8- double negative (DN) stage to CD4+CD8+ double positive (DP) stage prior to the formation of CD4+ helper and CD8+ cytolytic T cells ready for circulation. Each developmental stage is tightly regulated by sequentially operating molecular networks, of which only limited numbers of transcription regulators have been deciphered. Here, we identified Zfp335 transcription factor as a new player in the regulatory network controlling thymocyte development in mice. We demonstrate that Zfp335 intrinsically controls DN to DP transition, as T-cell-specific deficiency in Zfp335 leads to a substantial accumulation of DN3 along with reduction of DP, CD4+, and CD8+ thymocytes. This developmental blockade at DN stage results from the impaired intracellular TCRß (iTCRß) expression as well as increased susceptibility to apoptosis in thymocytes. Transcriptomic and ChIP-seq analyses revealed a direct regulation of transcription factors Bcl6 and Rorc by Zfp335. Importantly, enhanced expression of TCRß and Bcl6/Rorc restores the developmental defect during DN3 to DN4 transition and improves thymocytes survival, respectively. These findings identify a critical role of Zfp335 in controlling T-cell development by maintaining iTCRß expression-mediated ß-selection and independently activating cell survival signaling.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Linfócitos T
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Sobrevivência Celular
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Receptores de Antígenos de Linfócitos T alfa-beta
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Elife
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China